A 29-mRNA host response test from blood accurately distinguishes bacterial and viral infections among emergency department patients

Abstract

Background: Whether or not to administer antibiotics is a common and challenging clinical decision in patients with suspected infections presenting to the emergency department (ED). We prospectively validate InSep, a 29-mRNA blood-based host response test for the prediction of bacterial and viral infections.

Methods: The PROMPT trial is a prospective, non-interventional, multi-center clinical study that enrolled 397 adult patients presenting to the ED with signs of acute infection and at least one vital sign change. The infection status was adjudicated using chart review (including a syndromic molecular respiratory panel, procalcitonin and C-reactive protein) by three infectious disease physicians blinded to InSep results. InSep (version BVN-2) was performed using PAXgene Blood RNA processed and quantified on NanoString nCounter SPRINT. InSep results (likelihood of bacterial and viral infection) were compared to the adjudicated infection status.

Results: Subject mean age was 64 years, comorbidities were significant for diabetes (17.1%), chronic obstructive pulmonary disease (13.6%), and severe neurological disease (6.8%); 16.9% of subjects were immunocompromised. Infections were adjudicated as bacterial (14.1%), viral (11.3%) and noninfected (0.25%): 74.1% of subjects were adjudicated as indeterminate. InSep distinguished bacterial vs. viral/noninfected patients and viral vs. bacterial/noninfected patients using consensus adjudication with AUROCs of 0.94 (95% CI 0.90-0.99) and 0.90 (95% CI 0.83-0.96), respectively. AUROCs for bacterial vs. viral/noninfected patients were 0.88 (95% CI 0.79-0.96) for PCT, 0.80 (95% CI 0.72-89) for CRP and 0.78 (95% CI 0.69-0.87) for white blood cell counts (of note, the latter biomarkers were provided as part of clinical adjudication). To enable clinical actionability, InSep incorporates score cutoffs to allocate patients into interpretation bands. The Very Likely (rule in) InSep bacterial band showed a specificity of 98% compared to 94% for the corresponding PCT band (> 0.5 µg/L); the Very Unlikely (rule-out) band showed a sensitivity of 95% for InSep compared to 86% for PCT. For the detection of viral infections, InSep demonstrated a specificity of 93% for the Very Likely band (rule in) and a sensitivity of 96% for the Very Unlikely band (rule out).

Conclusions: InSep demonstrated high accuracy for predicting the presence of both bacterial and viral infections in ED patients with suspected acute infections or suspected sepsis. When translated into a rapid, point-of-care test, InSep will provide ED physicians with actionable results supporting early informed treatment decisions to improve patient outcomes while upholding antimicrobial stewardship. Registration number at Clinicaltrials.gov NCT03295825.

Keywords: Acute infection; Diagnostics; Emergency department; Gene expression; Host response; InSep; Sepsis.

Conflict of interest statement

James W. Wacker, Sabrina M. Coyle, Henry K. Cheng, Oliver Liesenfeld, and Timothy E. Sweeney are employees of, and shareholders in Inflammatix. The other authors have no conflicts of interest to declare. E.J. Giamarellos-Bourboulis has received honoraria from Abbott CH, Angelini Italy, InflaRx GmbH, MSD Greece, XBiotech Inc., and B·R·A·H·M·S GmbH (Thermo Fisher Scientific); independent educational grants from AbbVie Inc, Abbott CH, Astellas Pharma Europe, AxisShield, bioMérieux Inc, Novartis, InflaRx GmbH, Swedish Orphan BioVitrum AB and XBiotech Inc; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis).

Figures

Fig. 1

Study flowchart. 400 patients with suspected acute infection and ≥ 1 vital sign (VS) changes from six EDs in Greece were enrolled. Three physicians used electronic health records (EHRs) data alongside results from PCT, CRP, and respiratory syndromic panels to establish ground truths for the presence of bacterial and viral infections. InSep performance was compared to ground truths

Fig. 2

InSep testing accuracy using consensus adjudication. a InSep bacterial scores and b InSep viral scores among patients with known bacterial, viral, and non-infected status as determined by three-physician consensus adjudication. c Area under the receiver operating curves (AUROCs) for InSep bacterial scores (bacterial vs. viral/noninfected predictions). d Area under the receiver operating curves (AUROCs) for InSep viral scores (viral vs. bacterial/noninfected predictions). (E) Bacterial vs. viral/noninfected AUROCs for InSep bacterial scores, procalcitonin, C-reactive protein, and white blood cell counts

Fig. 3

InSep interpretation bands provide clinically actionable results. a InSep bacterial results in interpretation bands ranging from Very likely, Possibly to Unlikely and Very unlikely. b Performance accuracy for procalcitonin depicted in interpretation bands for different concentration ranges reported in the literature [31]. c InSep viral results in interpretation bands ranging from Very likely, Possibly to Unlikely and Very unlikely

Fig. 4

InSep bacterial (x-axis) and viral (y-axis) scores for 97 patients with confirmed SARS-CoV-2 infection. Patients with microbiologically confirmed bacterial (co-)infection are depicted in red (circled)